Prostate Cancer and Osteoporosis – What’s the Link?

What do prostate cancer and osteoporosis—which is often considered a woman’s disease—have in common? The two most important factors are (1) men are at risk for getting both of these diseases as they grow older, especially around age 65 and beyond; and (2) men who are being treated for prostate cancer with hormone therapy (also called hormone deprivation therapy and androgen deprivation therapy), regardless of age, are at increased risk of developing osteoporosis. Hormone therapy reduces levels of androgens (mainly the hormones testosterone and dihydrotestosterone) produced by the body.

What is osteoporosis?

Osteoporosis is a disease in which the bones lose density or mass. It is referred to as a silent disease because most people don’t know they have it until they break a bone or they have a bone density test that reveals the bone loss.

A bone’s strength depends on both its size and density, and bone density is based in part on how much calcium, phosphorus, and other minerals the bones contain. Bone density is also determined by hormone levels. In women, the dramatic decline in estrogen levels at menopause has a significant impact on bone loss, as women lose about half the total amount of bone of their entire lives during the first ten years after menopause. In men, low levels of testosterone can cause bone loss as well, but these hormone levels typically decline gradually—at a rate of about 1 percent per year in men age 30 and older–unless their production is significantly reduced, as it is with hormone deprivation therapy for prostate cancer.

Other risk factors for osteoporosis include:

• Use of certain medications such as glucocorticoids
• Not getting enough calcium (calcium should come from food, not supplements)
• Insufficient physical exercise
• Smoking
• Drinking too much alcohol
• Having a family history of the disease
• Being thin or having a slight frame

Osteoporosis in men

Although osteoporosis is more common in older women, it affects older men as well. The American College of Physician reports that osteoporosis affects an estimated 7 percent of white men, 5 percent of African-American men, and 3 percent of Hispanic men in the United States. (Qaseem 2008)

Osteoporosis is a serious problem for both men and women. Although the risk of osteoporosis may seem secondary to dealing with prostate cancer, experiencing a broken bone, especially if it affects a hip, can significantly reduce survival. Men are usually older than women when they have a fracture, yet complications and death associated with hip fracture in men are three times higher than they are in women.

One of the main causes of osteoporosis in men is hypogonadism, which occurs when the testes produce little or no testosterone. A major cause of male hypogonadism is hormone therapy for prostate cancer.

Affect of hormone therapy for prostate cancer on bones

Hormone deprivation therapy is designed to deprive cancer cells of male hormones (androgens), primarily testosterone, which the cancer needs to grow. However, this approach also has a detrimental impact on bone, because testosterone and estrogen protect against bone loss. When testosterone is blocked by hormone therapy, bones lose density and are more likely to break. Research indicates, for example, that up to 20 percent of men who are on hormone therapy for localized prostate cancer will experience a fracture within 5 years. (Adler 2011)  An editorial from the Journal of Clinical Oncology in 2008 noted that approximately one-third of the estimated 2 million prostate cancer survivors in the United States were being treated with the most commonly used hormone therapy for prostate cancer (Smith 2008) (see “Hormone Therapy for Prostate Cancer” below).

At one time, hormone therapy was mostly prescribed for men whose prostate cancer was more advanced and had spread to other parts of the body. In more recent years, however, prostate cancer is more often being diagnosed in its early stages, and so some men are choosing hormone therapy earlier in the course of the disease. This means they are also exposing themselves to a greater risk of osteoporosis earlier in life.

Of special concern is the number of men who are receiving hormone therapy for prostate cancer and who are not monitoring their bone mineral density (BMD) for risk of osteoporosis. A glimpse of this problem is apparent from the results of a study published in the January 2011 issue of the Consultant Pharmacist. In it, the investigators identified all male veterans who had received hormone deprivation therapy between October 1, 2005 and September 30, 2009, and whether they had been screened at any time for bone mineral density. Only 22.8 percent of the veterans had been screened, despite the known high risk for bone loss. (D’Alesio 2011) An earlier study published in the Journal of General Internal Medicine also found that only one-third of men being treated with hormone deprivation therapy for prostate cancer received any type of screening, prevention, or treatment for osteoporosis. (Yee 2007)

Four types of hormone therapy are used for men with prostate cancer:

• Drugs called luteinizing hormone-releasing hormone agonists (LH-RH agonists; also known as gonadotropin-release hormone [GnRH] agonists) are the primary choice for treating metastatic prostate cancer, and they are also used for many men who have locally advanced or recurrent nonmetastatic prostate cancer.  LH-RH agonists, which include Lupron, Viadur, and Zoladex, dramatically reduce the production of testosterone. However, their side effects include the risk of osteoporosis, hot flashes, erectile dysfunction, and reduced libido.
• Anti-androgens are another type of hormone therapy for prostate cancer patients that can block production of testosterone. These drugs include bicalutamide (Casodex), flutamide (Eulexin), and nilutamide (Nilandron). Anti-androgens work to block production of the small amount of testosterone produced by the adrenal glands, and so they are used along with LH-RH agonists to starve prostate cancer cells. Side effects include diarrhea, erectile dysfunction, breast development, and dizziness.
• A third type of hormone therapy is estrogen, which is used infrequently because it is associated with significant side effects, such as blood clots, chest pain, breast development, depression, and headache. Estrogen therapy is usually limited to men who have not responded to other hormonal approaches.
• Unlike the three types of hormone therapy already mentioned, the fourth type—orchiectomy surgery to remove the testicles—is not reversible. Orchiectomy permanently stops testosterone production from the testes, and thus is used only as a last resort.

How to prevent and treat osteoporosis

If you are undergoing hormone therapy for prostate cancer, you and your doctor need to discuss how you will manage the bone loss associated with the therapy. The approach you take will depend on several factors, including the state of your bone density at the time you begin hormone therapy, whether you have any other medical conditions, your ability to exercise, how long you will need to take the hormone therapy, and other factors.

One of the main ways to help prevent and treat osteoporosis is with medication. The Food and Drug Administration has approved numerous drugs for treating men with osteoporosis and to increase bone mineral density in men who are on hormone deprivation therapy for prostate cancer. In addition, there are several off-label agents used for the same purpose.

Osteoporosis drugs for men

Most of the medications prescribed for women for osteoporosis also can be used by men, although not all of them have FDA approval for use in males.

• Bisphosphonates are drugs that slow the rate of bone loss and can also lead to an increase in bone density. The bisphosphonate drugs, which include alendronate (Fosamax), ibandronate (Boniva) risedronate (Actonel), and zoledronic acid (Reclast), have been approved by the FDA for use in men and can be taken either orally or intravenously. Most bisphosphonates are taken orally daily, once or twice a week, or once a month. Zoledronic acid is given intravenously (IV) once a year while one form of ibandronate is typically given IV every 3 months. An example of the effectiveness of bisphosphonates can be seen in a randomized controlled trial of 112 men with prostate cancer who were given alendronate for one year. At the end of the year, bone mineral density had increased in the hip by 2.3 percent and in the spine by 5.1 percent. (Greenspan 2007)
• Selective estrogen receptor modulator (SERM) medications help oppose the actions of estrogen in the body, slow bone thinning, and can cause some increase in bone thickness. The two SERMs prescribed for off-label use in men are raloxifene (Evist) and toremifene (Fareston). A recent double-blind, placebo-controlled Phase II study conducted at Massachusetts General Hospital Cancer Center evaluated the use of toremifene in 646 men receiving hormone deprivation therapy for prostate cancer versus placebo in 638 men. At the end of the two-year study, the incidence of new vertebral fractures was 4.9 percent in the placebo group and 2.5 percent in the toremifene group. Toremifene also significantly improved bone mineral density, bone turnover markers, and serum lipid levels. (Smith 2010)
• Teriparatide (Forteo) is a synthetic form of the natural parathyroid hormone FDA approved for use in men (and postmenopausal women) who have severe osteoporosis. The drug forms new bone and increases both bone mineral density and bone strength, which subsequently reduces the risk of fracture. Teriparatide is taken once daily as a subcutaneous injection.
• Denosumab (Prolia) is a humanized monoclonal antibody and antiresorptive agent that works by reducing the activity of a specific receptor activator. The drug has FDA approval for postmenopausal women with osteoporosis, and it is used off-label for men on hormone deprivation therapy. Denosumab has been shown to increase bone density and decrease vertebral fractures in men who are on hormone therapy. (Adler/Gill 2011) This injectable drug is administered every six months.
• Calcitonin is a naturally occurring hormone that helps regulate calcium levels and slows the rate of bone thinning. This medication can be taken by injection or nasal spray. Calcitonin is not often used by men for treatment of osteoporosis.

Side effects of osteoporosis drugs for men

• Bisphosphonates: Common side effects include heartburn and irritation of the esophagus if you are taking pills. The IV forms of bisphosphonates may cause constipation, diarrhea, headache, flatulence, joint pain, and muscle pain. In rare cases, bisphosphonates can cause severe or incapacitating bone, joint, and/or muscle pain.
• SERMs: The most common side effects are fatigue, hot flashes, mood swings, and night sweats.
• Teriparatide: When you first start using teriparatide, you may experience dizziness or rapid heartbeat within 4 hours of injecting teriparatide, and the symptoms may persist for a few minutes to a few hours. This effect typically resolves after a few doses as your body adjusts to the medication. Other side effects may include muscle cramps, spasms, pain, swelling, and or bruising at the injection site. If any of these symptoms persist, contact your physician. Unlikely serious side effects may include constipation, fainting, mental or mood changes and unusual tiredness.
• Denosumab: The most common side effects are back pain, cystitis, high cholesterol (hypercholesterolemia), musculoskeletal pain, and pain in the extremities. Less common are constipation, serious infections, and osteonecrosis of the jaw.
• Calcitonin: Common side effects include nasal discomfort, sores, or redness, nosebleeds, and runny nose.

Other ways to prevent and treat osteoporosis

• Better nutrition: A diet rich in whole, natural foods and calcium from foods (rather than supplements) is important for bone health. Adequate amounts of vitamin D from sunshine and/or supplements is also essential for proper absorption of calcium. The Prostate Diet is an excellent nutrition plan to follow.
• Exercise more: Weight-bearing exercise prompts bone tissue to become stronger. Regular exercise, such as walking, dancing, weight training, and tennis can help prevent bone loss.
• Quit smoking and drinking: Smoking causes the body to absorb less calcium from the diet, while heavy consumption of alcohol weakens bones and increases the risk of fracture.
• Bone mineral density test: The most widely used test to measure bone mineral density is the dual-energy x-ray absorptiometry (DXA) test, which is typically used to monitor bone density in the hip and spine. However, forearm DXA may be important in men who are taking hormone therapy, along with monitoring of the hip and spine. DXA is a painless test that is similar to an x-ray but delivers much less radiation. Any man who is on hormone deprivation therapy should ask their doctor for a bone density test.

Clinical trials

Men with prostate cancer who are undergoing hormone deprivation therapy may be interested in participating in a clinical trial that is exploring the use of osteoporosis drugs in this population. Anyone interested in such clinical trials should ask their healthcare provider about available studies or they can go to the Clinical trial.gov website and search for trials that are recruiting volunteers.

Men with prostate cancer who are undergoing some form of hormone deprivation therapy are at risk for development of osteoporosis. Therefore this population of men should take steps to help prevent bone loss by discussing their alternatives with a knowledgeable healthcare provider and institute measures as soon as possible to protect their bone health and prevent osteoporosis.

References

Adler RA. Management of osteoporosis in men on androgen deprivation therapy. Maturitas 2011 Feb;68(2):143-7.

Adler RA, Gill RS. Clinical utility of denosumab for treatment of bone loss in men and women. Clin Interv Aging 2011; 6:119-24

D’Alesio V et al. Evaluation of osteoporosis risk assessment in veterans receiving androgen-deprivation therapy. Consult Pharm 2011 Jan; 26(1): 43-47

Greenspan SL et al. Effect of once-weekly oral alendronate on bone loss in men receiving androgen deprivation therapy for prostate cancer: A randomized trial. Ann Intern Med 2007; 146: 416-24

Medical Letter. Drugs for postmenopausal osteoporosis. Treatment Guidelines from the Medical Letter, 2008; 6(74): 67-74

Qaseem A et al. Pharmacologic treatment of low bone density or osteoporosis to prevent fractures: a clinical practice guideline from the American College of Physicians. Ann Intern Med 2008 Sep 16; 149(6): 404-15

Smith MR et al. Toremifene to reduce fracture risk in men receiving androgen deprivation therapy for prostate cancer. J Urol 2010 Oct; 184(4): 1316-21

Smith MR. Osteoporosis in men with prostate cancer: now for the fracture data. J Clin Oncol 2008; 26(2): 4371-72

WebMD: Osteoporosis in men

Yee EF et al. Osteoporosis management in prostate cancer patients treated with androgen deprivation therapy. J Gen Intern Med 2007 Sep; 22(9): 1305-10